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  • WHO suggests live birth has birth weight 500 gm, gestational age of 22 weeks, and body length of 25 cm “ any sign of life” criteria Fetal heart rate Breathing Movement of voluntary muscles 350 g is 50 th percentile for 20 weeks gestation TCA Fetal death reported when ≥500 g or ≥22 weeks Birth and death certificates are not generated after miscarriage ability to call a fetal loss a stillbirth is important
  • 6.2/1000 live births and fetal deaths (total births = live births+fetal deaths) AA have 2x risk stillbirth Some of this increase can be attributed to access to and quality of medical care Even with adequate access , still have higher rate of stillbirth Higher rates diabetes, HTN, abruption, PPROM
  • In July 2009 the Urban Child Institute in Memphis looked at the discrepancies in still births in Tennessee counties Concluded that differences were related to reporting different GA/weight
  • Between 24-27 weeks, most common cause if stillbirth is infection (19%) Contribution of infection to stillbirth rate is difficult to define Some pathogens clearly causally associated with stillbirth Parvo CMV Toxo Other pathogens might be associated with increased risk of stillbirth but strong evidence of causal relation is absent Ureaplasma urealyticum Mycoplasma hominis GBS
  • Nulliparity OR 1.2 – 1.4
  • 24-27 weeks, most common cause still birth Infection Stillbirth related to infection occur most frequently in fetuses <1000 g Abruption Anomalies 21% unexplained Stillbirth related to abruption has decreased over decades After 28 weeks, unexplained stillbirth increases Fetal death that is unexplained by fetal, placental, maternal, or obstetric factors represents 25-60% of all fetal deaths Diagnosis of exclusion Depends on rigorousness of stillbirth assessment
  • Diagnostic criteria for determining if a fetal death is due to an infection are not well defined and complicated by high frequency of asymptomatic maternal vaginal colonization of some potential pathogens.
  • Stillbirth rate 4x higher than singletons
  • Childbearing increasing among older women Older women are at increased risk for adverse outcomes Low birth weight Preterm Fetal mortality Significant proportion of perinatal deaths in older women are related to lethal congenital and chromosomal abnormalities Increased risk of unexplained stillbirth late in pregnancy persists in older women even after controlling for risk factors such as HTN, DM, previa, multiple gestation AMA remains as independent risk factor after accounting for medical conditions that occur in older women Increased risk associated with anomalies has been reduced with prenatal diagnostic testing and availability of abortions Peak rise period in older mothers between 37-41 weeks but NO studies to examine differential risk antepartum vs intrapartum
  • Mature gravidas at increased risk of various adverse outcomes Low birth weight Preterm SGA Stillbirth Link between advanced maternal age and stillbirth but little information on timing of in utero death Stillbirth defined In utero death > 20 weeks Excluded congenital malformations and chromosomal abnormalities Women 35-39 were more than 2-fold as likely to experience intrapartum stillbirth while those 40 or greater were 3x as likely Highest risk of stillbirth exhibited among mothers in oldest age group Higher levels of obstetric complications in older women could contribute to elevated risk for still birth Information on pregnancy complications not readily available in this data base Etiologic factors for antepartum and intrapartum stillbirth have been suggested to be different Preeclampsia, HTN, abnormal placental conditions are more likely to cause antepartum stillbirth Excess of these conditions in older women may explain 4-fold increment in occurrence of antepartum stillbirth among older women Intrapartum stillbirth more likely to result from fetal distress, obstructed labor Indication of access to and quality of care during delivery Different risk estimates for antepartum vs intrapartum stillbirth with maternal age may reflect dynamics in distribution and patterns of these etiologic factors as women age
  • Thinner women may be better able to perceive fetal movement Hyperlipidemia Increased endothelial dysfunction Platelet aggregation Clinically significant atherosclerosis Sleep studies show obese women snore more and have increased apnea-hypoxia events Increased episodes oxygen destauration Snoring associated with pregnancy induced hypertension and growth restriction
  • Karyotypic analysis underestimates genetic contribution to stillbirth 50% karyotype cell culture unsuccessful
  • One of several studies which challenge association between thrombophilia and complications No difference in study and control group Findings are consistent with studies from Germany and Austria
  • Most important tests in still birth evaluation Autopsy Identification of birth defects and morphologic abnormalities suggesting genetic or developmental abnormalities Determine and/or confirm other causes of stillbirth Infection Anemia Hypoxia Metabolic abnormalities Comparative genomic hybridization Scan genome for differences from normal reference genome without mitotic activity Detects only copy number changes relative to the average in the entire specimen Does not detect triploidy No information on chromosome architecture Cannot discern translocation from non-dysjunction Down’s Does not detect balanced chromosomal rearrangements Only detects changes in substantial percentage of cells
  • After autopsy and histologic evaluation, pathologist can proceed with appropriate culture and nucleic acid specimens for bacteria and viruses taken for organisms suspected on basis of histology Parvovirus serology may be useful Implicated in meaningful proportion of cases RPR Syphilis is a generally accepted cause of stillbirth TORCH serology questionable Toxo, rubella, CMV, HSV Traditionally advised but titers rarely clinically useful Routine placental bacterial cultures may be useful but problematic Avoid vaginal wall contamination Culture between membranes Ureaplasma and mycoplasma in addition to aerobic and anaerobic cultures may be useful Incidence in live-born pregnancies unknown Nucleic acid based tests for bacterial or viral products may be more sensitive but also associated with more false positive results
  • FMH common cause of stillbirth – screening advised KBT Fetal cells in maternal blood Elution of hemoglobin from adult cells Acid resistant fetal hemoglobin remains intact Statistical imprecision in quantifying FMH
  • Testing cases characterized by placental insufficiency appropriate given apparent pathophysiology of these conditions Limited evidence that treatment in subsequent pregnancy improves outcomes Some heritable thrombophilias are present in a large proportion of normal individuals – positive test may be unrelated to stillbirth
  • Recurrent stillbirth 2 unexplained previous stillbirths at 37 and 38 weeks 35 weeks gestation with decreased FM 3 days after negative CST D/C’d home after reactive NST Returned 16 hours later with no FM x 5 hrs IUFD confirmed
  • Nonrecurring conditions Testing of limited value Affected mothers better served with screeening, education, counseling Recur but not predictable Unlikely to benefit from testing in subsequent pregnancies.
  • Rates of delivery for abnormal or equivocal testing were 16.3% at or before 39 weeks and 1% before 36 weeks
  • Must be considered in any strategy that may lead to iatrogenic late preterm birth
  • Stillbirth

    1. 1. Stillbirth N.L. Meyer University of Tennessee
    2. 2. Definitions <ul><li>Fetal death </li></ul><ul><ul><li>Death prior to the complete expulsion or extraction from its mother of a product of human conception, irrespective of the duration of pregnancy and which is not an induced termination of pregnancy 1 </li></ul></ul><ul><li>Delivery of a fetus showing no signs of life </li></ul><ul><ul><li>Absence of breathing, heart beat, umbilical cord pulsations, definitive voluntary movements </li></ul></ul><ul><ul><li>Excludes </li></ul></ul><ul><ul><ul><li>Transient cardiac contractions </li></ul></ul></ul><ul><ul><ul><li>Fleeting respiratory efforts (gasps) </li></ul></ul></ul>1 National Center for Health Statistics
    3. 3. Definitions <ul><li>Not all fetal deaths are stillbirths </li></ul><ul><li>World Health Organization </li></ul><ul><ul><li>Fetal death late in pregnancy </li></ul></ul><ul><ul><li>Allows each country to define gestational age at which fetal death is considered stillbirth </li></ul></ul><ul><ul><ul><li>16 to 28 weeks </li></ul></ul></ul><ul><li>National Center for Health Statistics </li></ul><ul><ul><li>Most states use 20 weeks or a fetal weight of ≥ 350 g or ≥ 500 g </li></ul></ul><ul><ul><li>28 weeks (late stillbirth) </li></ul></ul><ul><li>Tennessee Code Annotated </li></ul><ul><ul><li>Fetal death ≥ 500 g or in the absence of weight, ≥ 22 completed weeks gestation </li></ul></ul>
    4. 4. Incidence <ul><li>> 3 million stillbirths each year worldwide </li></ul><ul><li>2005 rate of 6.2/1000 total births in US </li></ul><ul><li>Rate of early stillbirth has remained stable </li></ul><ul><li>Rate of late fetal loss has decreased by 29% since 1990 </li></ul><ul><li>African Americans have 2x stillbirth rate as Caucasians </li></ul><ul><ul><li>DM, HTN, abruption, PPROM </li></ul></ul>
    5. 5. Urban Child Institute <ul><li>July 2009 report </li></ul><ul><ul><li>Variation in 2006 Infant Mortality in Tennessee </li></ul></ul><ul><li>No universal method for calculating IMR </li></ul><ul><ul><li>Discrepancies in reports may be artificial </li></ul></ul><ul><ul><li>Wide variation in reporting practices among counties </li></ul></ul><ul><li>Suggest Tennessee Office of Vital Records implement criteria to differentiate fetal death vs live birth vs infant death </li></ul><ul><ul><li>American Academy of Pediatrics </li></ul></ul><ul><ul><ul><li>Threshold for live birth 400 gm or 23 weeks </li></ul></ul></ul>
    6. 6. Etiology <ul><li>Unknown in 25 – 60% of cases </li></ul><ul><li>Identifiable causes can be attributed to </li></ul><ul><ul><li>Maternal conditions </li></ul></ul><ul><ul><li>Fetal conditions </li></ul></ul><ul><ul><li>Placental conditions </li></ul></ul>
    7. 7. Maternal Conditions <ul><li>Prolonged pregnancy </li></ul><ul><li>Diabetes (poorly controlled) </li></ul><ul><li>SLE </li></ul><ul><li>APAS </li></ul><ul><li>Infection </li></ul><ul><li>HTN </li></ul><ul><li>Preeclampsia </li></ul><ul><li>Eclampsia </li></ul><ul><li>Hemoglobinopathy </li></ul><ul><li>AMA </li></ul><ul><li>Rh disease </li></ul><ul><li>Uterine rupture </li></ul><ul><li>Maternal trauma or death </li></ul><ul><li>Inherited thrombophilia </li></ul>
    8. 8. Fetal conditions <ul><li>Multiple gestation </li></ul><ul><li>IUGR </li></ul><ul><li>Congenital anomaly </li></ul><ul><li>Genetic abnormality </li></ul><ul><li>Infection </li></ul><ul><li>Hydrops </li></ul>
    9. 9. Placental Conditions <ul><li>Cord accident </li></ul><ul><li>Abruption </li></ul><ul><li>PROM </li></ul><ul><li>Vasa previa </li></ul><ul><li>Fetomaternal hemorrhage </li></ul><ul><li>Placental insufficiency </li></ul>
    10. 10. Maternal Risk Factors Sickle cell disease Multiple gestation Malaria Smoking Poor nutritional status Infection – Parvovirus B19, syphilis, streptococcal infection, listeria Congenital anomalies Hypertensive disease, preeclampsia Hypertensive disease – complications of preeclampsia and eclampsia Medical disease – diabetes, SLE, renal disease, thyroid, cholestasis Infection – syphilis and gram-negative infection Growth restriction/placental anomalies Obstructed prolonged labor and associated asphyxia, infection, injury Congenital and karyotypic anomalies Developing Countries Developed Countries
    11. 11. Risk Factors in Developed Countries <ul><li>Non-Hispanic black race </li></ul><ul><li>Nulliparity </li></ul><ul><li>Advanced maternal age </li></ul><ul><li>Obesity </li></ul>ACOG Practice Bulletin #102 March 2009
    12. 12. Most Frequent Types of Stillbirth According to GA Fretts et al. Ob Gyn 1992;79:35-9 Fretts and Usher. Contem Rev Ob Gyn 1997;9:173-9 Abruptio placenta (12%) Abruptio placenta (18%) Anomalies (14%) Fetal malnutrition (14%) Fetal malnutrition (19%) Abruptio placenta (14%) Unexplained (40%) Unexplained (26%) Infection (19%) 37+ weeks 28 - 37 weeks 24 - 27 weeks
    13. 13. Infection <ul><li>Most common cause of stillbirth 24 – 27 weeks </li></ul><ul><li>Contribution to stillbirth rate is difficult to define </li></ul><ul><li>Some pathogens are clearly causally related </li></ul><ul><ul><li>Parvo B-19 </li></ul></ul><ul><ul><li>CMV </li></ul></ul><ul><ul><li>Toxoplasmosis </li></ul></ul><ul><li>Some are associated with stillbirth but absent evidence of causal relationship </li></ul><ul><ul><li>Ureaplasma urealyticum </li></ul></ul><ul><ul><li>Mycoplasma hominis </li></ul></ul><ul><ul><li>GBS </li></ul></ul><ul><ul><li>Colonization common among healthy women </li></ul></ul>
    14. 14. Infection <ul><li>Most stillbirths occur in premature fetuses </li></ul><ul><ul><li>19% of stillbirths < 28 weeks </li></ul></ul><ul><ul><li>2% of stillbirths at term </li></ul></ul><ul><li>No change despite widespread use of antibiotics </li></ul><ul><li>Viral pathogens are the most common source of hematogenous infection of the placenta </li></ul><ul><ul><li>Fetal death resulting from maternal infection is rare </li></ul></ul><ul><ul><li>Diagnostic criteria are not well defined </li></ul></ul><ul><ul><li>High frequency of asymptomatic maternal colonization </li></ul></ul>
    15. 15. Multiple Gestations <ul><li>19.6 / 1,000 stillbirth rate (4x singletons) </li></ul><ul><li>Complications specific to multiple gestations </li></ul><ul><ul><li>TTTS </li></ul></ul><ul><li>Increased risk of common complications </li></ul><ul><ul><li>AMA </li></ul></ul><ul><ul><li>Fetal anomalies </li></ul></ul><ul><ul><li>Growth restriction </li></ul></ul>
    16. 16. Advanced Maternal Age <ul><li>Lethal congenital and chromosomal anomalies </li></ul><ul><li>Medical complications associated with age </li></ul><ul><ul><li>Multiple gestations </li></ul></ul><ul><ul><li>HTN </li></ul></ul><ul><ul><li>DM </li></ul></ul><ul><li>AMA is an independent risk factor </li></ul><ul><li>Unexplained fetal demise is the only type that is statistically more common (late pregnancy) </li></ul>
    17. 17. Advanced Maternal Age Antepartum vs Intrapartum Maternal age (yrs) Rate per 1000 Saliu et al. J Obstet Gynaecol 2008;34:843
    18. 18. Obesity (BMI ≥ 30) <ul><li>Increased risk </li></ul><ul><li>Behavioral, socioeconomic and obstetric factors </li></ul><ul><ul><li>Smoking, diabetes, preclampsia </li></ul></ul><ul><li>Risk remains even after controlling for above </li></ul><ul><li>Theories </li></ul><ul><ul><li>Perception of fetal movements </li></ul></ul><ul><ul><li>Hyperlipidemia </li></ul></ul><ul><ul><li>Apnea – hypoxia events </li></ul></ul>
    19. 19. Obesity 11 / 1000 ≥ 40 8 / 1000 30 – 39.9 5.5 / 1000 < 30 Stillbirth Rate per 1000 BMI
    20. 20. Chromosomal Abnormalities <ul><li>Abnormal karyotype found in 8 – 13% stillbirths </li></ul><ul><ul><li>> 20% with anatomic abnormalities or growth restriction </li></ul></ul><ul><ul><li>4.6% with normally formed fetuses </li></ul></ul><ul><li>Most common abnormalities </li></ul><ul><ul><li>Monosomy X (23%) </li></ul></ul><ul><ul><li>Trisomy 21 (23%) </li></ul></ul><ul><ul><li>Trisomy 18 (21%) </li></ul></ul><ul><ul><li>Trisomy 13 (8%) </li></ul></ul><ul><li>Karyotypic analysis underestimates risk </li></ul>
    21. 21. Chromosomal Abnormalities Korteweg et al 2008 Ob Gyn 111;865 28% Fetal tissue sampling 85% Amniocentesis / CVS Success Rate Method
    22. 22. Fetal Tissue <ul><li>Umbilical cord – 32.1% </li></ul><ul><li>Fascia lata – 29.9% </li></ul><ul><li>Cartilage – 24.2% </li></ul><ul><li>Fetal blood – 22.2% </li></ul><ul><li>Pericardium – 0% </li></ul><ul><li>Other tissue – 19.2% </li></ul><ul><ul><li>Placenta, skin, unknown </li></ul></ul>
    23. 23. Chromosomal Abnormalities Korteweg et al 2008 Ob Gyn 111;865
    24. 24. Cord Accidents <ul><li>30% of normal pregnancies </li></ul><ul><li>Account for only 2.5% of stillbirths in autopsy case series </li></ul><ul><li>Attribution requires </li></ul><ul><ul><li>Cord occlusion and hypoxic tissue on autopsy </li></ul></ul><ul><ul><li>Exclusion of other causes </li></ul></ul><ul><li>Actual proportion remains uncertain </li></ul>
    25. 25. Thrombophilia <ul><li>Relationship with late fetal death is more consistent than with early losses </li></ul><ul><li>Have been associated with late loss but lack of evidence of causal relationship </li></ul><ul><li>Inconsistent studies </li></ul><ul><ul><li>OR range from 1.8 to 12 </li></ul></ul><ul><li>Thrombophilias are not uncommon </li></ul><ul><ul><li>15 – 25% of Caucasian populations </li></ul></ul>
    26. 26. Thrombophilia <ul><li>Some but not all studies show a relationship with adverse outcomes </li></ul><ul><li>Most are retrospective or case-controlled </li></ul><ul><ul><li>Prospective longitudinal studies are needed </li></ul></ul><ul><li>Inappropriate or no controls </li></ul><ul><li>No evaluation for other causes </li></ul><ul><li>At least one type of thrombophilia is seen in 30% of normal controls </li></ul>
    27. 27. Thrombophilia Gonen R et al. Absence of association of inherited thrombophilia with unexplained third-trimester intrauterine fetal death. AJOG 2005;192:742-6
    28. 28. Evaluation <ul><li>Fetal autopsy </li></ul><ul><ul><li>Single most useful test </li></ul></ul><ul><li>Examination of placenta, cord and membranes </li></ul><ul><li>Karyotype evaluation </li></ul><ul><ul><li>8 – 13% of stillbirths </li></ul></ul><ul><ul><li>Comparative genomic hybridization </li></ul></ul><ul><ul><ul><li>Useful when fetal cells cannot be cultured </li></ul></ul></ul>
    29. 29. Infection <ul><li>Autopsy and histologic evaluation of placenta, membranes, and cord provide best evidence of infectious etiology </li></ul><ul><li>Value of routine cultures and serology is controversial </li></ul><ul><li>Parvovirus serology </li></ul><ul><li>Screening for syphilis </li></ul><ul><li>TORCH titers questionable utility </li></ul><ul><li>Placental culture problematic </li></ul><ul><ul><li>Incidence in live birth is unknown </li></ul></ul><ul><ul><li>DNA test associated with false positives </li></ul></ul>
    30. 30. Hematologic Etiology <ul><li>Fetal – maternal hemorrhage </li></ul><ul><ul><li>Kleihauer-Betke test </li></ul></ul><ul><ul><li>Typically underestimates fetal cell count with large FMH </li></ul></ul><ul><li>Red cell alloimmunization </li></ul><ul><ul><li>Indirect Coombs’ test </li></ul></ul><ul><ul><li>Autopsy and placenta assessment useful </li></ul></ul>
    31. 31. Thrombophilia <ul><li>Routine testing is controversial </li></ul><ul><li>Evidence to support limited testing </li></ul><ul><ul><li>Evidence of placental insufficiency </li></ul></ul><ul><ul><ul><li>IUGR </li></ul></ul></ul><ul><ul><ul><li>Placental infraction </li></ul></ul></ul><ul><ul><li>Recurrent fetal loss </li></ul></ul><ul><ul><li>Personal or family history of thrombosis </li></ul></ul>
    32. 32. Medical Complications <ul><li>Exclude clinically overt diabetes and thyroid dysfunction </li></ul><ul><ul><li>GDM has stillbirth rate similar to normal </li></ul></ul><ul><ul><li>Subclinical thyroid disease has not been proven as cause of still birth </li></ul></ul><ul><li>Screening for subclinical disease is of unproven benefit </li></ul>
    33. 33. Silver et al. Work-up of stillbirth: a review of the evidence. AJOG 2007;196:433-444.
    34. 34. Antepartum Surveillance <ul><li>Little evidence-based data to guide testing with previous unexplained stillbirth </li></ul><ul><ul><li>32 – 34 weeks </li></ul></ul><ul><ul><li>2 – 4 weeks before gestational age of previous still birth </li></ul></ul><ul><li>Most subsequent pregnancies have a favorable outcome </li></ul><ul><li>Increased risk of iatrogenic prematurity </li></ul>
    35. 35. Antepartum Surveillance <ul><li>300 women with previous stillbirth </li></ul><ul><ul><li>49% unexplained </li></ul></ul><ul><li>1 recurrent stillbirth despite reassuring testing </li></ul><ul><ul><li>Perinatal mortality 3.3/1000 </li></ul></ul><ul><li>Earliest delivery associated with a positive test result was 32 weeks </li></ul>Weeks et al. Antepartum surveillance for a history of stillbirth: When to begin. AJOG 1995;172:486-92.
    36. 36. Antepartum Testing Protocol Weeks et al.
    37. 37. <ul><li>Protocol may not be appropriate for all previous stillbirths </li></ul><ul><ul><li>Nonrecurring conditions </li></ul></ul><ul><ul><ul><li>Perinatal infection </li></ul></ul></ul><ul><ul><ul><li>Fetal anomalies </li></ul></ul></ul><ul><ul><ul><li>Maternal trauma </li></ul></ul></ul><ul><ul><li>Stillbirths following OB complications that can recur but cannot be predicted </li></ul></ul><ul><ul><ul><li>Abruption </li></ul></ul></ul><ul><ul><ul><li>Prolapse </li></ul></ul></ul><ul><ul><ul><li>Uterine rupture </li></ul></ul></ul>Antepartum Testing Protocol
    38. 38. ACOG Practice Bulletin #102 <ul><li>Little evidence-based data to guide antepartum surveillance with prior unexplained stillbirth </li></ul><ul><li>Antepartum testing may be initiated at 32 – 34 weeks </li></ul><ul><li>Associated with potential morbidity and costs </li></ul><ul><ul><li>16.3% delivery at or before 39 weeks </li></ul></ul><ul><ul><li>1% delivery before 36 weeks </li></ul></ul>Management of Stillbirth March 2009
    39. 39. ACOG Practice Bulletin #102 <ul><li>Antenatal testing before 37 weeks gestation </li></ul><ul><ul><li>1.5% rate of iatrogenic prematurity for intervention based on false-positive test </li></ul></ul><ul><li>Excess risk of infant mortality due to late preterm birth </li></ul><ul><ul><li>8.8 / 1000 at 32 – 33 weeks gestation </li></ul></ul><ul><ul><li>3 / 1000 at 34 – 36 weeks gestation </li></ul></ul>